Process for the preparation of thienamycin and intermediates

ABSTRACT

Disclosed is a process for the total synthesis of thienamycin from L-aspartic acid via intermediate III: ##STR1##

This is a division of application Ser. No. 457,792 filed Jan. 13, 1983,which is a division of Ser. No. 262,657 filed May 11, 1981, now U.S.Pat. No. 4,378,315, which is a division of Ser. No. 154,190 filed May29, 1980, now U.S. Pat. No. 4,290,947, which is a continuation of Ser.No. 034,052 filed Apr. 27, 1979, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to the total synthesis of the known antibioticthienamycin (I). ##STR2##

Starting from L-aspartic acid, the synthesis proceeds in astereo-selective way via intermediates II, III, IV: ##STR3## wherein Xis a conventional leaving group and R is hydrogen, a conventional,readily removable protecting group or a salt cation. The details of thetotal synthesis are given below.

DETAILED DESCRIPTION OF THE INVENTION

The process of the present invention may conveniently be summarized bythe following reaction diagram: ##STR4## In words relative to the abovediagram, L-aspartic acid 1 is esterified according to well knownprocedures. Typically 1 in a solvent such as benzene, toluene,chloroform or the like is treated with an esterifying agent such asbenzyl alcohol, methanol, ethanol, ispropanol, or the like in thepresence of p-toluene sulfonic acid, HCl, HBr, or the like at atemperature of from 0° to 110° C. for from 1 to 24 hours to achieve thedesired establishment and hence protection of the carboxyl functions.The resulting species 2 in a solvent such as ether, THF, DME or the likeis treated with trimethylchlorosilane, or the like followed by treatmentwith EtMgBr, MeMgI, φMgBr, t-BuMgCl, or the like at a temperature offrom -40° to 50° C. for from 1 to 72 hours to provide azetidinone 3.Reduction of species 3 with a reducing agent such as NaBH₄, or the likein a solvent such as methanol, ethanol, isopropanol or the like at atemperature of from -10° to 40° C. for from 1 to 6 hours provides 4.(For purposes here, the symbols: Et, Me, φ, iPr, and t-Bu stand for:ethyl, methyl, phenyl isopropyl, and tert-butyl, respectively.)

Treatment of 4 in a solvent such as methylene chloride, CHCl₃ or thelike with methane sulfonyl chloride, methane sulfonic anhydride or thelike in the presence of a base such as Et₃ N, iPr₂ NEt, or the likefollowed by treatment with a stoichiometric to 5 fold excess of sodiumiodide in acetone yields 5 via 4a.

The transformation 5→6 establishes the protecting group R¹ which may bea triorganosilyl group, such as t-butyldimethylsilyl,t-butyldiphenylsilyl, triphenylsilyl, isopropyldimethylsilyl, forexample, or may be 3,4-dimethoxybenzyl, for example. Silyl protection ispreferred, and typically R¹ is established by treating 5 in a solventsuch as dimethylformamide, acetonitrile, hexamethylphosphoramide,tetrahydrofuran and the like with a silylating agent such ast-butyldimethylchlorosilane, t-butyldiphenylchlorosilane,triphenylchlorosilane, and the like at a temperature of from -20° to 25°C. for from 0.5 to 24 hours in the presence of a base such astriethylamine, diisopropylethylamine, or imidazole.

The transformation 6→7 is accomplished by treating 6 in a solvent suchas tetrahydrofuran, dimethoxyethane, diethylether or the like with acarbanion generically represented by the following structure: ##STR5##wherein M is a metal cation such as lithium, potassium, copper ormagnesium, for example, and R², R³ and R⁴ are selected from alkyl, arylor aralkyl such as methyl, ethyl, benzyl, methoxybenzyl, trityl andphenyl, for example, at a temperature of from -100° to 0° C. and from0.5 to 4 hours. Typically, the carbanion reagent is prepared prior toaddition of substrate 6 on treatment of the triorganothiomethane with astrong base such as n-butyllithium, t-butyllithium, phenyllithium,lithium diisopropylamide (LDA) or the like.

The alkylation 7→8 is accomplished by treating 7 in a solvent such astetrahydrofuran, dimethoxyethane, diethylether, hexamethylphosphoramide,at a temperature of from -100° to -20 C. with a strong base such aslithium diisopropylamide, lithium hexamethyldisilazide, lithium2,2,6,6-tetramethylpiperidide, potassium hydride or the like followed bythe addition of an equivalent to 10 fold excess of acetaldehyde. Thisreaction gives a mixture of isomers from which the desired trans-R formcan be conveniently separated by chromatography or crystallization.

The transformation 8→9 is accomplished by treating 8 in a solvent suchas methanol, ethanol, isopropanol, water or the like at a temperature offrom 0° to 80° C. with a Lewis acid such as mercuric chloride, silvertetrafluoroborate, thallium trinitrate or the like. The value of R⁵ isdetermined by the identity of the alcohol taken in reaction.

The transformation 9→10 establishes the hydroxyl protecting group R².The most preferred protecting groups R² are triorganosilyl groups suchas t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl and thelike. Typically, silylation is accomplished by treating 9 with thecorresponding triorganosilyl chloride in a solvent such asdimethylformamide, acetonitrile, tetrahydrofuran and the like at atemperature of from -20° to 80° C. for from 0.5 to 24 hours.

The reduction 10→11 is accomplished by treating 10 in a solvent such astoluene, methylene chloride diethylether, tetrahydrofuran and the likewith a reducing agent such as diisobutylaluminum hydride, sodiumbis(2-methoxyethoxy)aluminum hydride or the like at a temperature offrom -100° to -40° C. for from 1 to 10 hours.

The addition 11→12 is accomplished by treating 11 in a solvent such astetrahydrofuran, diethylether, dimethoxyethane or the like at atemperature of from -100° to 0° C. for from 15 minutes to 2 hours in thepresence of LiCH₂ CO₂ R⁶ ; wherein R⁶ is benzyl, p-methoxybenzyl,2,4-dimethoxybenzyl or the like; which reagent is typically generated insitu on treatment of the appropriate R⁶ acetate with a strong base suchas LDA, lithium hexamethyldisilazide, lithium2,2,6,6-tetramethylpiperide, or the like.

If desired, a more readily removable carboxyl protecting group mayconveniently replace the first established group, R⁶, by the carboxylprotecting group R⁷. This transformation 12→13→14 is accomplished byselectively deblocking 12 to form 13 by hydrogenation or hydrolysis.Typically, the reaction is accomplished by treating 12 in a solvent suchas methanol, ethanol, dioxane, tetrahydrofuran, water or the like undera hydrogenation pressure of from 1 to 4 atmospheres in the presence of acatalyst such as Pd on charcoal, Pd(OH)₂, or the like for from 0.1 to 10hours. The 13 intermediate (M may be H, Na, K or ammonium such as Et₃NH, for example) need not be isolated. Intermediate 14 is obtained fromthe hydrogenation mixture upon treatment with the chosen reagentcalculated to establish R⁷ such as an aralkyl halide in a solvent suchas dimethylformamide, acetonitrile, hexamethylphosphoramide at atemperature of from 0° to 50° C. for from 0.5 to 18 hours. R⁷ istypically an aralkyl group such as p-nitrobenzyl, or o-nitrobenzyl, forexample.

The oxidation 14→15 is accomplished by treating 14 in a solvent such asmethylene chloride, acetonitrile, or the like with an oxidizing systemsuch as dipyridine chromium (VI) oxide, 3,5-dimethylpyrazole chromium(VI) oxide, pyridinium chlorochromate, pyridinium dichromate,trifluoroacetic anhydride-dimethylsulfoxide, acetic anhydride-dimethylsulfoxide or the like at a temperature of from -78° C. to 25° C. forfrom 5 min. to 8 hrs.

Removal of protecting groups R¹ and R² (15→16) is accomplished by acidicaqueous hydrolysis of 15 in a solvent such as methanol, ethanol,tetrahydrofuran, dioxane or the like in the presence of an acid such ashydrochloric, sulfuric, acetic or the like at a temperature of from 0°to 100° C. for from 2 to 18 hours.

The diazo species 17 is prepared from 16 by treating 16 in a solventsuch as CH₃ CN, CH₂ Cl₂, THF or the like with an azide such asp-carboxybenzenesulfonylazide, toluenesulfonylazide,methanesulfonylazide or the like in the presence of a base such astriethylamine, pyridine, (C₂ H₅)₂ NH or the like for from 1 to 50 hoursat 0°-25° C.

Cyclization (17→18) is accomplished by treating 17 in a solvent such asbenzene, toluene, THF or the like at a temperature of from 50°-110° C.for from 1-5 hours in the presence of a catalyst such asbis(acetylacetonato)Cu (II) [Cu(acac)₂ ], CuSO₄, Cu powder, Rh(OAc)₂, orPd(OAc)₂. Alternatively, the cyclization may be accomplished byirradiating 17 through a pyrex filter (a wave length greater than 300nm) in a solvent such as benzene, CCl₄, diethylether or the like at atemperature of from 0°-25° C. for from 0.5 to 2 hours. ["OAc"=acetate.]

Establishment of leaving group X (18→19) is accomplished by acylatingthe keto ester 18 with an acylating agent R°X such as P-toluenesulfonicacid anhydride, p-nitrophenylsulfonic acid anhydride,2,4,6-triisopropylphenylsulfonic acid anhydride, methanesulfonic acidanhydride, toluenesulfonyl chloride, p-bromophenylsulfonyl chloride, orthe like wherein X is the corresponding leaving group such as toluenesulfonyloxy, p-nitrophenylsulfonyloxy, methanesulfonyloxy,p-bromophenylsulfonyloxy and other leaving groups which are establishedby conventional procedures and are well known in the art. Typically, theabove acylation to establish leaving groups X is conducted in a solventsuch as methylene chloride, acetonitrile or dimethylformamide, in thepresence of a base such as diisopropylethylamine, triethylamine,4-dimethylamino-pyridine or the like at a temperature of from -20° to40° C. for from 0.5 to 5 hours. The leaving group X of intermediate 19can also be halogen. The halogen leaving group is established bytreating 18 with a halogenating agent such as φ₃ PCl₂, φ₃ PBr₂, (φO)₃PBr₂, oxalyl chloride or the like in a solvent such as CH₂ Cl₂, CH₃ CN,THF, or the like in the presence of a base such asdiisopropylethylamine, triethylamine, or 4-dimethylaminopyridine or thelike. [φ=phenyl.]

The reaction 19→20 is accomplished by treating 19 in a solvent such asdioxane, dimethylformamide, dimethylsulfoxide, acetonitrile,hexamethylphosphoramide, or the like in the presence of an approximatelyequivalent to excess of the mercaptan reagent HSCH₂ CH₂ NHR⁸ wherein R⁸is hydrogen or a readily removable N-protecting group such asp-nitrobenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, or the like in thepresence of a base such as sodium hydrogen carbonate, potassiumcarbonate, triethylamine, diisopropylethylamine, or the like at atemperature of from -40° to 25° C. for from 1 to 72 hours. The mercaptanreagent, HSCH₂ CH₂ NHR⁸, is typically prepared by treatingaminoethylmercaptan in the presence of the desired acid chloride in thepresence of a base such as sodium bicarbonate, sodium hydroxide, or thelike in a solvent such as aqueous diethylether, aqueous dioxane, aqueousacetone, or the like at a temperature of from 0° to 25° C. for from 0.5to 4 hours.

The final deblocking step 20→I is accomplished by conventionalprocedures such as hydrolysis or hydrogenation. Typically 20 in asolvent such as dioxane-water-ethanol, tetrahydrofuran-aqueousdipotassium hydrogen phosphate-isopropanol or the like is treated undera hydrogen pressure of from 1 to 4 atmospheres in the presence of ahydrogenation catalyst such as palladium on charcoal, palladiumhydroxide, or the like at a temperature of from 0° to 50° C. for from0.5 to 4 hours to provide I.

In the above-discussed aldol reaction 7→8 for introduction of thehydroxyethyl side chain, the scheme proceeds directly to give a mixtureof isomers (trans-R, trans-S, and cis R) from which the desired trans-Risomer can be separated chromatographically or by crystallization. Anindirect aldol reaction scheme stereo-selectively provides the desiredtrans-R isomer according to the following scheme: ##STR6## wherein allsymbols are as previously defined.

In words relative to the above reaction scheme, Step A has beendescribed above. The direct acetylation, Step B, is accomplished bytreating 7 with two or more equivalents of a base such as lithiumdiisopropylamide, lithium hexamethyldisilazide, lithium2,2,6,6-tetramethylpiperidide, in a solvent such as tetrahydrofuran,diethylether, or dimethoxyethane, for example, at a temperature of from-100° to -20° C. with an acylating agent such as N-acetyl imidazole orthe like. Addition of the 7 plus base mixture to the acylating agent ispreferred.

The oxidation Step C is accomplished with an oxidizing agent such asdipyridine chromium(VI)oxide, trifluoroaceticanhydride-dimethylsulfoxide-triethylamine, pyridinium dichromate, aceticanhydride-dimethylsulfoxide in a solvent such as methylene chloride,acetonitrile, or the like at a temperature of from -78° to 25° C. forfrom 5 minutes to 5 hours.

The reduction Step D is accomplished by contacting the ketone with areducing agent such as potassium tri(sec-butyl)borohydride, lithiumtri(sec-butyl)borohydride, sodium borohydride, sodiumtris(methoxyethoxy)aluminum hydride, lithium aluminum hydride or thelike in a solvent such as diethylether, tetrahydrofuran, toluene or thelike at a temperature of from -20° to 25° C. The reaction canconveniently be conducted in the presence of an added complexing saltsuch as potassium iodide, magnesium bromide or the like.

In the foregoing word description of the above schematic reactiondiagram for the total synthesis of thienamycin, it is to be understoodthat there is considerable latitude in selection of precise reactionparameters. Suggestion of this latitude and its breadth is generallyindicated by the enumeration of equivalent solvent systems, temperatureranges, protecting groups, and range of identities of involved reagents.Further, it is to be understood that the presentation of the syntheticscheme as comprising distinct steps in a given sequence is more in thenature of a descriptive convenience than as a necessary requirement; forone will recognize that the mechanically dissected scheme represents aunified scheme of synthesis and that certain steps, in actual practice,are capable of being merged, conducted simultaneously, or effected in areverse sequence without materially altering the progress of synthesis.

The following examples recite a precise scheme of total synthesis. It isto be understood that the purpose of this recitation is to furtherillustrate the total synthesis and not to impose any limitation.

EXAMPLE 1 Preparation of 4(S)-4-Iodomethylazetidin-2-one STEP A ##STR7##Benzyl (S)-azetidin-2-one-4-carboxylate

To a 1000 ml separatory funnel are added dibenzyl (S)-aspartatep-toluenesulfonic acid salt (48.6 g, 0.1 mole), ice-cold diethyl ether(300 ml), ice-cold water (100 ml), and ice-cold saturated aqueouspotassium carbonate (50 ml). The mixture is shaken vigorously and thelayers are separated. The aqueous portion is extracted with more colddiethyl ether (2×100 ml). The combined ether solution is washed withbrine, dried with magnesium sulfate, and evaporated under vacuum toprovide dibenzyl (S)-aspartate (31.4 g, 0.1 mole) as a colorless liquid.

The dibenzyl (S)-aspartate in anhydrous diethyl ether (200 ml) is cooledin an ice-bath under a nitrogen atmosphere. Trimethylchlorosilane (12.7ml, 0.1 mole) is added to the stirred solution to give a whiteprecipitate. Triethylamine (14.0 ml, 0.1 mole) is then added to themixture. The cooling bath is removed and the mixture is stirred at roomtemperature (22°-25° C.) for 2 hrs. The mixture is then filtereddirectly into a 3-neck, 1.0 liter, round bottom flask fitted with asintered glass funnel, magnetic sitrrer, and a vacuum-nitrogen inlet.This operation is carried out under a blanket of nitrogen, care beingtaken to exclude atmospheric moisture. The sintered glass funnel isreplaced by a stopper and the ether is evaporated under vacuum withstirring to provide dibenzyl (S)-N-trimethylsilyl-aspartate (35.5 g,0.092 mole) as a slightly hazy oil.

Anhydrous diethyl ether (250 ml) is added to the flask containing thesilyl derivative and the magnetic stirrer is replaced by a mechanicalstirrer. The resulting solution is stirred under a nitrogen atmospherewith ice-bath cooling. Ethereal ethyl magnesium bromide (34 ml of a2.94M solution, 0.1 mole) is added dropwise over 40 min. to give a creamcolored, stirable precipitate. The cooling bath is removed and themixture is stirred at room temperature. After 1.5 hrs, a viscous gumforms. The mixture is allowed to stand overnight at room temperature.The mixture is then cooled in an ice-methanol bath while ammoniumchloride saturated 2N hydrochloric acid (100 ml) is added slowly withstirring. The resulting mixture is diluted with ethyl acetate (100 ml)and water (100 ml) and the layers are separated. The aqueous portion isextracted with more ethyl acetate (3×100 ml). The combined organicsolution is washed with water (200 ml), 5% aqueous sodium bicarbonatesolution (100 ml), water (100 ml), and brine, dried with magnesiumsulfate, and filtered. Evaporation of the solvent under vacuum gives anorange oil interspersed with a fine, granular precipitate (25.3 g). Thismaterial is dissolved in warm chloroform (75 ml), diluted with petroleumether (125 ml), seeded, scratched, and cooled in an ice-bath. Theprecipitate is collected, washed with petroleum ether, and dried undervacuum to give benzyl (S)-azetidin-2-one-4-carboxylate (3.85 g) as anoff-white solid mp 136°-139° C. The mother liquors and washings arecombined, diluted with petroleum ether to 500 ml, seeded, and left in arefrigerator for several days. The resulting precipitate is collected,washed with petroleum ether, and dried under vacuum to give additionalproduct (0.82 g) as pale yellow crystals. Recrystallization of a samplefrom chloroform-petroleum ether gave the product as small, white flakes:mp 141°-143°; [α ]_(D) =-43.4° (c3.275 in CHCl₃); IR(CHCl₃) 3425, 1778,1746 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 3.00 (ddd, 1,J=1.9, 3.2, and 14.6 Hz,H-3a), δ 3.35 (ddd, 1, J32 1.5, 5.4, and 14.6 Hz, H-3b), δ 4.20 (dd, 1,J=3.2 and 5.4 Hz, H-4), δ 5.22 (s, 2, OCH₂ Ph), δ 6.48 (m, 1, NH), 7.38(s, 5, phenyl); mass spectrum m/e 205 (M+), 163, 91, 70, 43.

Anal. Calcd. for C₁₁ H₁₁ NO₃ : C, 64.38; H, 5.40; N, 6.83. Found: C,64.10; H, 5.70; N, 6.77.

STEP B ##STR8## 4(S)-4-Hydroxymethylazetidin-2-one

Sodium borohydride (3.69 g, 97.5 mmol) is added in one portion to asuspension of benzyl 4(S)-azetidin-2-one-4-carboxylate (20.0 g, 97.5mmol) in 300 ml of absolute methanol at 0° C. The mixture is thenallowed to warm slowly with periodic cooling being supplied to keep theinternal temperature <30° C. After stirring for 2 hr., glacial aceticacid (23.4 g, 390 mmol) is added and the reaction mixture isconcentrated under vacuum. The residue is treated with 500 ml ofchloroform and filtered. The filtrate is concentrated under vacuum andthe residue is chromatographed on 250 g of silica gel (4:1,chloroform:methanol) to yield 9.62 g (98%) of4(S)-hydroxymethylazetidin-2-one as a white solid: m.p. 51°-53° C.;[α]_(D) =+68.0° (C=2.676 in CHCl₃); IR (CHCl₃) 3410, 1765 cm⁻¹ 1H NMR(CDCl₃ ) δ 7.07 (1H, br. s, NH), δ 4.05 (1H, br. s, OH), δ 3.77 (2H, mH4, H-5a or b), δ 3.58 (1H, dd, J=11, 6, H-5a or b), δ 2.97 (1H, ddd,J=14.5, 4.8, 1.3, H3b), δ 2.7 (1H, br. d, J=14.5, H3a); mass spectrumm/e 101 (M+), 83.

STEP C ##STR9## 4(S)-4-Methanesulfonyloxymethyl azetidin-2-one

Methane sulfonyl chloride (11.46 g, 100 mmol) is added dropwise bysyringe to a solution of 4(S)-4-hydroxymethyl azetidin-2-one (10.1 g,100 mmol) and triethyl amine (10.1 g, 100 mmol) in 15 ml of drymethylene chloride at 0° C. (Warming is necessary in order to initiallysolubilize the alcohol. The resulting solution is then cooled to 0° C.prior to addition of the other reagents). The resulting solution isstirred at 0° C. for 1 hr. during which time a voluminous precipitate isproduced. At the end of this time, the reaction mixture is filtered andthe filtrate is concentrated under vacuum. The two solid residues arecombined and treated with 500 ml of chloroform. The resulting mixture isfiltered to yield substantially pure 4(S)-4-methanesulfonyloxymethylazetidin-2-one as a white solid. The filtrate, which contains most ofthe triethylamine hydrochloride, is concentrated under vacuum andchromatographed on 200 g of silica gel (4:1 chloroform:methanol) toyield an additional quantity of mesylate. This material is combined withthat obtained previously and recrystallized from chloroform to yield15.57 g (87%) of 4(S)-4-methanesulfonyloxymethylazetidin-2-one ascolorless needles: m.p. 109.5°-110.5° C.; [α]_(D) =+25.8° (C=1.025 in H₂O);

NMR (D₂ O) δ 4.62 (1H, dd, J=11.2, 3.0, H-5a or b), δ 4.43 (1H, dd,J=11.2, 6, H-5a or b), ##STR10## δ 3.19 (1H, dd, J=15, 4.5, H3b).

δ 2.88 (1H, dd, J=15, 2.5, H3a); mass spectrum m/e 179 (M+), 136;

Anal: Calc: C, 33.51; H, 5.06; N, 7.82; s, 17.89. Found: C, 33.54; H,5.08; N, 7.72; s, 17.93.

STEP D ##STR11## 4(S)-4-Iodomethylazetidin-2-one

A mixture of 4(S)-4-methanesulfonyloxy azetidin 2-one (11.8 g, 65.9mmol) and powdered sodium iodide (19.8 g, 132 mmol) in 130 ml of acetoneis heated at reflux for 6 hr. The resulting reaction mixture isconcentrated in vacuo, treated with 200 ml of chloroform and filtered.The filtrate is washed with 2×50 ml of water and dried over magnesiumsulfate. The organic phase is filtered, concentrated in vacuo, andchromatographed on 250 g of silica gel (ethyl acetate) to yield 11.94 g(86%) of 4(S)-4-iodomethyl-azetidin-2-one as a white solid. Thismaterial is recrystallized from ether-petroleum ether to yield whitecrystals: mp 91°-92° C.; [α]_(D) =-23.7° (C=1.354 in CHCl₃); IR (CHCl₃)3450, 1765 cm⁻¹, 1H NMR (CHCl₃) δ 6.13 (brs, N-H), δ 3.94 (m, 1H, Hc), δ3.36 (m, 2H, Hd and e), δ 3.16 (ddd, 1H, J=14.9, 5.4, 2.3, Ha), δ 2.72(d, d, d, 1H, J=14.9, 2.1, 2, Hb) mass spectrum m/e 211 (M⁺), 168, 142,127, 84.

EXAMPLE 2 Preparation of(4S)-1-(t-Butyldimethylsilyl)-4-iodomethyl-azetidin-2-one ##STR12##t-butyldmethylchlorosilane (7.51 g, 49.8 mmol) is added in one portionto an ice-cold, stirring solution of (4S)-4-iodomethyl-azetidin-2-one(10.0 g, 47.4 mmol) and triethylamine (5.04 g, 49.8 mmol) in anhydrousdimethylformamide (100 ml). A voluminous white precipitate forms almostimmediately. The reaction mixture is stirred at 0°-5° for 1 hour andthen allowed to warm to room temperature. Most of the solvent is removedunder vacuum to give a residue which is partitioned between diethylether (250 ml) and water. The ethereal phase is washed with 2.5Nhydrochloride acid (50 ml), water (3×50 ml), and brine, dried withmagnesium sulfate, filtered, and evaporated under vacuum to provide(4S)-1-(t-butyldimethylsilyl)-4-iodomethyl-azetidin-2-one (15.1 g) as awhite solid. Recrystallization from petroleum ether--ethyl ether givesthe product as colorless plates, mp 71°-72°; n.m.r. (CDCl₃), δ 3.8(m,l), δ 2.6-3.6 (2 overlapping d of AB, 4) δ 1.0 (S, 9), δ 0.3 (S, 6),δ 0.25 (S, 6). EXAMPLE 3 Preparation of(4S)-1-(t-Butyldimethylsilyl)-4-(2,2,2-tri(methylthio)-ethyl)azetidin-2-one##STR13## n-Butyllithium (19.4 ml of 2.5M hexane solution, 48.5 mmol) isadded slowly by syringe to a solution of tri(methylthio)methane (7.47 g,48.5 mmol) in 150 ml of freshly distilled THF at -78° C. The resultingsolution is stirred at -78° C. for 30 min. prior to the addition of asolution of (4S)-1-(tert-butyldimethylsilyl)-4-iodomethylazetidin-2-one(15.0 g, 46.15 mmol) in 50 ml of THF. This solution is stirred at -78°C. for 30 min., then quenched by addition of saturated aqueous ammoniumchloride solution. The reaction mixture is allowed to warm to roomtemperature, then poured into ether (250 ml), washed with water (2×100ml) brine (100 ml) and dried over magnesium sulfate. Removal of solventsin vacuo gives an oil which is crystallized from pertroleum ether togive 13.3 g (82%) of(4S)-1-(t-butyldimethylsilyl)-4-(2,2,2-tri(methylthio)ethyl)azetidin-2-oneas colorless prisms. m.p. 61°-62° C. IR(CHCl₃, CM⁻¹) 2918, 2850, 1730;n.m.r. (CDCl₃) δ 4.0 (m,l), δ 3.35 (dd, 1, J=5.5, 16), δ 2,83 (dd, 1,J=3,16) δ 2,5 (ABq, 2) δ 2,15 (s, 9), δ 0.98 (s, 9), δ 0.25 (s, 6).EXAMPLE 4 Preparation of(3S,4R)-1-(t-butyldimethylsily)-3-[(R)-1-hydroxyethyl]-4-[2,2,2-tri(methylthio)ethyl]-azetidin-2-one##STR14## n-Butyllithium (14.8 ml of 2.5N hexane solution, 37.0 mmol) isadded by syringe to a solution of diisopropylamine (3.74 g, 37.0 mmol)in 180 ml of freshly distilled tetrahydrofuran at -78° C. The resultingsolution is stirred at -78° C. for 15 min prior to the addition of asolution of(4S)-1-(t-butyldimethylsilyl)-4-[2,2,2-tri(methylthio)ethyl]azetidin-2-one(12.34 g, 35.16 mmol) in 35 ml of tetrahydrofuran. This solution isstirred at -78° C. for 10 min prior to the addition of acetaldehyde(4.62 g, 105 mmol). The solution is stirred for an additional 5 min. at-78° C., and then quenched by addition of saturated aqueous ammoniumchloride solution, and allowed to warm to room temperature. The mixtureis poured into 250 ml of ether and washed with water (2×100 ml) andbrine and dried over magnesium sulfate. Removal of solutions in vacuogives an oil which is chromatographed on a silica gel column (1:1ether:petroleum ether) to give(3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-hydroxethyl]-4-[2,2,2-tri(methylthio)ethyl]-azetidin-2-one(7.0 g, 50.4%) at R_(f) =0.2. The product can be recrystallized frompetroleum ether. Alternatively, the trans R product can be isolated fromthe crude reaction mixture by direct crystallization from a petroleumether solution. EXAMPLE 5 Preparation of(3S,4R)-1-(t-Butyldimethylsilyl)-3-(1-oxoethyl)-4-[2,2,2-tri(methylthio)ethyl]azetidin-2-one##STR15##

A. n-Butyllithium (2.43 ml of 2.4 m solution, 5.84 mmol) is added bysyringe to a solution of diisopropylamine (591 mg, 5.84 mmol) in 25 mlof freshly distilled tetrahydrofuran at -78° C. The resulting solutionis stirred at -78° C. for 15 minutes prior to the addition of a solutionof(4R)-1-(t-butyldimethylsilyl)-4-[2,2,2-tri(methylthio)ethyl]azetidin-2-one(1.00 g, 2,85 mmol) in tetrahydrofuran (5 ml). This solution is stirredat -78° C. for 15 minutes, then added via a Teflon tube to a mixture ofN-acetylimidazole (642 mg, 5.84 mmol) in 25 ml of THF at -78° C. Theresulting yellow reaction mixture is stirred at -78° C. for 10 minutes,then quenched by addition of saturated aqueous ammonium chloridesolution. The mixture is diluted with ether (200 ml) and washed with2.5N hydrochloric acid solution (50 ml), water (50 ml) and brine (50 ml)and dried over magnesium sulfate. Removal of solvents in vacuo gives ayellow oil which is chromatographed on silica gel (30% ether inpetroleum ether) to yield(3S,4R)-1-(t-butyldimethylsilyl)-3-(1-oxoethyl)-4-[2,2,2-tri(methylthio)ethyl]azetidin-2-one.n.m.r. (CDCl₃) δ 4.42 (m, 1), δ 4.32 (d, 1) δ2.35 (m, 2), δ 2.32 (s, 3),δ 2.2 (s, 9), δ 0.98 (s, 9), δ 0.3 (2s, 6).

B. Trifluoroacetic anhydride (400 mg., 1.905 mmol) is added by syringeto a solution of dimethyl sulfoxide (2.53 mmol) in dry methylenechloride (5 ml) at -78° C. The resulting mixture is stirred at -78° C.for 30 minutes prior to the addition of a solution of(3RS,4R)-1-(t-butyldlimethylsilyl)-3-[(RS)-1-hydroxyethyl]-4-[2,2,2-tri(methylthio)ethyl]azetidin-2-one(500 mg., 1.27 mmol) in dry CH₂ cl₂ (1 ml). The resulting solution isstirred for 30 minutes prior to the addition of triethylamine (360 mg.,3.56 mmol). The cooling bath is removed. After 40 minutes, the reactionmixture is diluted with CH₂ Cl₂, washed with water and brine and driedover magnesium sulfate. Removal of solvents in vacuo gives an oil whichis purified as above. Yields 432 mg. (86%).

EXAMPLE 6 Preparation of(3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-hydroxyethyl]-4-[2,2,2-tri(methylthio)ethyl]azetidin-2-one##STR16## K-Selectride® (3.64 ml of 0.5M, 1.82 mmol) is added by syringeto a mixture of potassium iodide (126 mg., 0.758 mmol) and(3S,4R)-1-(t-butyldimethylsilyl)-3-(1-oxoethyl)-4-[2,2,2-tri(methylthio)ethyl]azetidin-2-one(298 mg, 0758 mmol) in freshly distilled ethyl ether (8 ml) at roomtemperature. The resulting mixture is stirred at room temperature for2.5 hours, then quenched by the addition of acetic acid (218 mg., 3.64mmol). The resulting mixture is diluted with ethyl acetate (25 ml) andfiltered through celite. Removal of solvents in vacuo gives an oil whichis chromatographed on silica gel (fether:petroleum ether) to yield 252mg of(3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-hydroxyethyl]-4-[2,2,2-tri(methylthio)ethyl]azetidin-2-one.N.M.R. (R isomer, CDCl₃ +D₂ O) δ 4.15 (dq, 1), δ 3.95 (ddd, 1, J=9.5,2.3), δ 3.26 (dd, 1, J=8, 2.3), δ 2.37 (m, 2), δ 2.16 (s, 9), δ 1.37 (d,3, J=6.6), δ 1.0 (s, 9), δ 0.26 (s, 6). EXAMPLE 7 Preparation of(3S,4R)-1-(t-Butyldimethylsilyl)-3-((R)-1-hydroxyethyl)-4-carbomethoxymethylazetidin-2-one##STR17## Mecuric chloride (12.37 g, 45.6 mmol) is added in one portionto a solution of(3S,4-R)-1-(t-butyldimethylsilyl)-3-[(R)-1-hydroxyethyl]-4-[2,2,2-tri(methylthio)ethyl]azetidin-2-one(6.0 g, 15.2 mmol) in 250 ml of absolute methanol at 0° C. The resultingmixture (heavy white precipitate) is stirred at 0° C. for 3 min., thenquenched by addition of sodium bicarbonate (8.99 g, 107 mmol). Thismixture is then filtered and the solid residue is washed with additionalmethanol. The combined filtrate and washings are concentrated in vacuoand the residue is partitioned between ethyl acetate and saturatedaqueous ammonium chloride solution. The organic phase is separated,washed with saturated aqueous ammonium chloride solution, water andbrine and dried over magnesium sulfate. Removal of solvents in vacuogives an oil which is chromatographed on a silica gel column (3:2cyclohexane:ethyl acetate) to yield(3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-hydroxyethyl)]-4-carbomethoxymethylazetidin-2-one.EXAMPLE 8 Preparation of(3S,4R)-1-(t-Butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-carbomethoxymethylazetidin-2-one##STR18## t-Butyldimethylchlorosilane (940 mg, 6.25 mmol) is added inone portion to a solution of(3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-hydroxyethyl]-4-carbomethoxymethylazetidin-2-one(1.88 g, 6.25 mmol) and triethylamine (1.27 g, 6.25 mmol) in 15 ml ofanhydrous diemthylformamide at 0° C. After 15 min. at 0° C. the coolingbath is removed and the reaction mixture is stirred at room temperaturefor 24 hrs. Ether (100 ml) is added and the mixture is filtered, thenwashed with 2.5N hydrochloric acid (20 ml), water (3×20 ml) and brine.The organic phase is dried over magnesium sulfate, then concentrated invacuo. The residue is chromatographed on silica gel (7:3 petroleumether:ether) to yield(3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-carbomethoxymethylazetidin-2-one.n.m.r. (CDCl₃) δ4.1 (m, 2), δ3.68 (S, 3), δ3.03 (dd, 1, J=4.3, 2.7),δ2.8 (ABq, 2), δ1.17 (d, 3, J=6.6), δ0.98 (s, 9), δ0.89 (s, 9), δ0.23(s, 6), δ0.1 (s, 6). EXAMPLE 9 Preparation of(3S,4R)-1-(t-Butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-(2-oxoethyl)azetidin-2-one##STR19## Diisobutylaluminum hydride (3.72 ml of 0.91M in hexane, 3.38mmol) is added slowly by syringe to a solution of(3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-carbomethoxymethylazetidin-2-one (936 mg, 2.26 mmol) in 25 ml of freshly distilled tolueneat -78° C. The resulting solution is stirred at -78° C. for 3 hrs., thenquenched by addition of 2.5N hydrochloric acid (5 ml). The resultingmixture is stirred for 2 min., then poured into a separatory funnelcontaining 100 ml of ether and 50 ml of 1.25N hydrochloric acidsaturated with tartaric acid. The organic phase is separated and theaqueous phase is extracted with ether (2×50 ml). The combined organicphases are washed with brine and dried over magnesium sulfate. Removalof solvents in vacuo gives a white solid which is recrystallized fromether-petroleum ether to give(3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-(2-oxoethyl)azetidin-2-one. m.p. 115°-116° C.; n.m.r. (CDCl₃) δ4.1 (m,1), δ4.03 (m, 1), δ2.7-3.2 (m, 3), δ1.23 (d, 3, J=6.4), δ1.08 (s, 9),δ0.9 (s, 9), δ0.25 (s, 6), δ0.1 (s, 6), δ9.83 (t, 1, J=1.4). EXAMPLE 10Preparation of(3S,4R)-1-(t-Butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-(3-benzyloxycarbonyl-2-hydroxypropyl)azetidin-2-one##STR20## n-Butyllithium (1.81 mmol) is added by syringe to a solutionof diisopropylamine (1.81 mmol) in 9 ml of freshly distilledtetrahydrofuran at -78° C. The resulting solution is stirred for 15 minat -78° C. Benzyl acetate (1.81 mmol) is then added dropwise by syringeand the resulting solution is stirred at -78° C. for 20 min. A solutionof(3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-(2-oxoethyl)azetidin-2-one(1.64 mmol) in 3 ml of anhydrous tetrahydrofuran is added slowly bysyringe. The reaction mixture is stirred at -78° C. an additional 15 minand then quenched by addition of saturated aqueous ammonium chloridesolution. Ethyl acetate (50 ml) is added and the organic phase isseparated, washed with water (2×10 ml) and brine and dried overmagnesium sulfate. Removal of solvents in vacuo gives a white solidwhich is chromatographed on a short silica gel column (40 % ether inpetroleum ether) to yield(3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-(3-benzyloxycarbonyl-2-hydroxypropyl)azetidin-2-one.n.m.r. (CDCl₃) δ7.32 (s, 5), δ5,1 (s, 2), δ4.0 (m, 3), δ2,4-3,8 (m, 4),δ2.0 (m, 2), δ1.25 (overlapping d, 3), δ0.95 (s, 9), δ0.9 (s, 9), δ0.3(s, 6), δ0.18 (s, 6). EXAMPLE 11 Preparation of(3S,4R)-1-(t-Butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-hydroxypropyl]azetidin-2-one##STR21## A mixture of(3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-(3-benzyloxycarbonyl-2-hydroxypropyl)azetidin-2-one(1.00 mmol), sodium bicarbonate (1.00 mmol) and 10% Pd/C in 20 ml of 4:1tetrahydrofuran-H₂ O is hydrogenated at 40 psi on a Parr shaker for 30min. The mixture is then filtered through Celite and the catalyst iswashed with 10 ml of water. The combined washings and filtrate areconcentrated i.v. to 2 ml and lyophilized. The resulting fluffy whitesolid is dissolved in 5 ml of anhydrous dimethylformamide andp-nitrobenzyl bromide (216 mg, 1.00 mml) is added in one portion. Theresulting solution is stirred at room temperature for 3 hrs, thendiluted with ether (50 ml) and washed with water (3×10 ml) and brine anddried over magnesium sulfate. The solvents are removed in vacuo and theresidue is chromatographed on silica gel to yield(3S,4R)-1-(t-butyldimethylsilyl) 3[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-hydroxypropyl]azetidin-2-one.n.m.r. (CDCl₃) δ7.85 (2d-aromatic, 4), δ5,26 (s, 2), δ4.2 (m, 3),δ2,5-3.6 (m, 4) δ2.0 (m, 2), δ1.4 (2 overlapping d, 3), δ1.0 (2s, 18),δ0.25 (2s, 12). EXAMPLE 12 Preparation of(3S,4R)-1-(t-Butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxopropyl]azetidin-2-one##STR22## Anhydrous chromium trioxide (10.0 mmol) is added to a soutionof anhydrous pyridine (20.0 mmol) in 30 ml of anhydrous methylenechloride. Ater stirring at room temperature for 15 min., the reactionmixture is treated all at once with a solution of(3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl-4-[3-(4-nitrobenzyl)oxycarbonyl-2-hydroxypropyl]-azetidin-2-one(1.00 mmol) in anhydrous methylene chloride (8 ml). The resultingmixture is stirred at room temperature for 5 min. The CH₂ Cl₂ layer isdecanted from the dark, tarry residue which is triturated with more CH₂Cl₂. The combined CH₂ Cl₂ phase is concentrated in vacuo. The residue istriturated with ether (100 ml) and the ether extracts are filtered. Thefiltrate is washed with 5% aqueous sodium bicarbonate solution, 2.5NHCl, 5% NaHCO₃ and brine, dried over magnesium sulfate and concentratedin vacuo to yield(3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxopropyl]azetidin-2-one. n.m.r.(CDCl₃) δ7.85 (2d-aromatic, 4), δ5.27 (s, 2), δ4.05 (m, 2), δ3.6 (s, 2),δ2.4-3.2 (dd overlapping ABq, 3) δ1.2 (d, 3, J=6.6), δ0.9 (2s, 18),δ0.22 (s, 6), δ0.05 (s, 6). EXAMPLE 13 Preparation of(3S,4R)-3-[(R)1-hydroxyethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxopropyl]azetidin-2-one##STR23##(3S,4R)-1-(t-butyldimethylsilyl)3-[(R)-1-(t-butyldimethylsilyoxy)ethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxopropyl]azetidin-2-one(7.9 mmol) is dissolved in 160 ml of 9:1 (v/v) methanol-water and cooledto 0° C. Concentrated hydrochloric acid (2.75 ml) is added and theresulting solution is stirred at 0° C. for 15 min., then allowed to warmto room temperature. The solution is stirred at room temperature for 2.5hrs, then diluted with ethyl acetate (200 ml) and washed with water,saturated aqueous sodium bicarbonate solution and brine, dried overmagnesium sulfate and concentrated in vacuo to yield(3S,4R)-3-[(R)1-hydroxyethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxopropyl]-azetidin-2-one.EXAMPLE 14 Preparation of(3S,4R)-3-[(R)-1-hydroxyethyl)-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxo-3-diazopropyl]azetidin-2-one##STR24## Triethylamine (263 mg, 2.6 mmol) is added by syringe to amixture of(3S,4R)-3-[(R)-1-hydroxyethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxopropyl]azetidin-2-one(253mg, 0.72 mmol) and p-carboxybenzene sulfonylazide (196 mg, 0.84 mmol) indry acetonitrile (6 ml) at 0° C. When addition is complete the coolingbath is removed and the reaction mixture is stirred at room temperaturefor 1 hour. The mixture is then diluted with ethyl acetate (50 ml) andfiltered. The filtrate is concentrated in vacuo and the residue ischromatographed on a short silica gel column (ethyl acetate) to yield222 mg, (81% overall from(3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxopropyl]azetidin-2-one)of(3S,4R)-3-(R)-1-hydroxyethyl)-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxo-3-diazopropyl]azetidin-2-oneas a white solid m.p. (dec.) 163° C. IR (CHCl₃, CM⁻¹) 3410, 2132, 1756,1718, 1650, 1350, 1280, 1120; n.m.r. (CDCl₃) δ7.9 (2d-aromatic, 4), δ5.4(s, 2), δ6.2 (brs, 1), δ4.1 (m, 2), δ2.6-3.6 (m, 4), δ1.32 (d, 3,J=6.2). EXAMPLE 15 Preparation of (5R,6S)p-Nitrobenzyl6-[(R)1-hydroxyethyl]-1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate##STR25## A suspension of(3S,4R)-3-[(R)-1-hydroxyethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxo-3-diazopropyl]azetidin-2-one(56.4 mg, 0.15 mmol) and rhodium (II) acetate (0.1 mg) in dry benzene (3ml) is deoxygenated by bubbling through nitrogen for 10 minutes. Themixture is then heated to 78° C. for 1 hour. During heating the solidstarting material gradually goes into solution. The mixture is thencooled, filtered to remove the catalyst, and the filtrate isconcentrated in vacuo to yield (5R,6S) p-nitrobenzyl6-[(R)-1-hydroxyethyl]-1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate,51 mg. (98%) as a colorless oil which slowly crystallized at roomtemperature (22° C.).

Physical Properties: ##STR26##

n.m.r.: (300 MHz, CDCl₃) δ8.26, 7.54 (aromatic, 4), 5.29 (AB, 2), 4.77(s, 1), 4.32 (dg, 1, J=6.6, 7), 4.16 (ddd, 1, J=7, 7.5, 2.2), 3.21 (dd,1, J=7, 2.2 ), 2.94 (dd, 1, J=19.5, 7) 2.50 (dd, 1, J=19.5, 7.5), 2.2(brs, 1), 1.37 (d, 3, J=6.6).

I.R.: (CHCl₃, CM⁻¹) 1770, 1758, 1610, 1522, 1353.

m.p. 110°-111° C.

EXAMPLE 16 Preparation of p-Nitrobenzyloxycarbonylaminoethanethiol##STR27##

To 600 ml diethyl ether (Et₂ O)-75 ml H₂ O in an ice bath with stirringis added 3.2 g cysteamine hydrochloride (mw=114; 28.1 mmole). A solutionof 7.14 g NaHCO₃ (mw=84; 85 mmole) in 75 ml H₂ O is added. The ice bathis removed, and at room temperature a solution of 6.75 gp-nitrobenzylchloroformate (mw=216; 31.3 mmole) in 270 ml Et₂ O is addeddropwise over a period of one hour. After 10 additional minutes, thelayers are separated. The ether layer is extracted with 150 ml 0.25NHCl, and then with 200 ml brine. Each aqueous layer is then backwashedsuccessively with 100 ml Et₂ O. The combined Et₂ O layers are dried overanhydrous MgSO₄, filtered, and concentrated under a N₂ stream. Thecrystalline residue is slurried in a small amount of ether, filtered,and the pale yellow crystals are dried under high vacuum to give 4.7 g.p-nitrobenzyloxycarbonylaminoethanethiol (65% yield).

NMR (CDCl₃): 8.18 (d, J=8 Hz, aromatic protons ortho to nitro), 7.47 (d,J=8 Hz, aromatic protons meta to nitro), 5.27 (--NH--), 5.20 (s, --CH₂--NH--), 2.67 (m, --CH₂ --SH), 1.35 (t, J=8.5 Hz, --SH) in ppm downfieldfrom TMS. IR (CHCl₃ solution): carbonyl-1725 cm⁻¹. M.S.: molecularion-256, (M-47 ) at 209, (M-136) at 120, ⁺ CH₂ φpNO₂ at 136.

EXAMPLE 17 Preparation of (5R,6S) p-Nitrobenzyl3-[2-(p-nitrobenzyloxycarbonyl)aminoethylthio]-6-[(R)-1-hydroxyethyl]-1azabicyclo[3,2,0]-hept-2-en-7-one-2-carboxylate##STR28## (5R,5S) p-Nitrobenzyl6-[(R)1-hydroxyethyl]-1-azabicyclo[3,2,0]heptan-3,7-dione-2-carboxylate(51 mg, 0.147 mmol) is dissolved in acetonitrile (3 ml) and theresulting solution is cooled to 0° C. Diisopropylethylamine (22 mg, 0.17mmol) is added by syringe and the resulting solution is stirred at 0° C.for 1 minute prior to the addition of a solution of freshlyrecrystallized p-toluene sulfonic anhydride (51 mg., 0.156 mmol) in dryacetonitrile (1 ml). The resulting solution is stirred at 0° C. for 1hour to provide (5R,6S)p-nitrobenzyl3-(p-toluenesulfonyloxy)-6-[(R)-1-hydroxyethyl]-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate,then cooled to -25° C. Diisopropylethylamine (80.5 mg, 0.624 mmol) isadded by syringe followed shortly thereafter by a solution ofN-p-nitrobenzyloxycarbonylcysteamine (40 mg, 0.156 mmol) in 1 ml of dryacetonitrile. The reaction mixture is then stored in a refrigerater for70 hr. The mixture is diluted with 25 ml of ethyl acetate washed withbrine and dried over magnesium sulfate. Solvents are removed in vacuo toyield a yellow oil which is chromatographed on a silica gel plate (ethylacetate, R_(f) =0.4) to yield (5R,6S)p-nitrobenzyl3-[2-(p-nitrobenzyloxycarbonyl)aminoethylthio]-6-[(R)-1-hydroxyethyl]-1-azabicyclo[3,2,0]-hept-2-en-7-dione-2-carboxylateas a yellow solid, m.p. 167°-169° C. IR (Nujol mull) 1773 and 1690 cm⁻¹; n.m.r. (CDCl₃) δ7.54-8.26 (overlapping ABq, 4), δ5.40 (ABq, 2), δ5.22(s, 2), δ4.27 (m, 2), δ3.47 (m), δ3.23 (dd, 1), δ3.14 (dd, 1) δ3.40 (dd,1), δ3.04 (m, 2), δ1.37 (d, 3). EXAMPLE 18 Preparation of Thienamycin##STR29## A mixture of N-p-nitrobenzyloxycarbonyl thienamycinp-nitrobenzyl ester (10 mg, 0.017 mmol) and 10% Pd/C-Bolhofer type intetrahydrofuran (2 ml), 0.1M dipotassium hydrogen phosphate solution(1.4 ml) and 2-propanol (0.2 ml) is hydrogenated at 40 psi on the Parrshaker for 30 minutes. The mixture is then filtered and the catalyst iswashed with water (3×3 ml). The combined filtrate and washings areextracted with ethyl acetate-ethyl ether then concentrated to ˜3 ml andlyophilized. The resulting white powder is identical to naturalthienamycin in all respects. EXAMPLE 19 Preparation of Benzyl(4-S)-azetidin-2-one-4-carboxylate ##STR30##

A mixture of dibenzyl (S)-aspartate p-toluenesulfonic acid salt (48.6 g,0.1 mole), diethylether (300 ml), water (100 ml), and saturated aqueouspotassium carbonate (50 ml) is shaken vigorously, The layers areseparated and the aqueous portion is extracted with more ether (2×100ml). The combined ethereal extracts are washed with brine, dried withmagnesium sulfate, filtered, and evaporated under vacuum to afforddibenzyl (S)-aspartate (31.5 g) as a water white liquid.

The dibenzyl (S)-aspartate in anhydrous diethyl ether (200 ml) is cooledin an ice bath and stirred under a nitrogen atmosphere whiletrimethylchlorosilane (12.7 ml, 0.1 mole) and triethylamine (14.0 ml,0.1 mole) are added successively over a few minutes. The cooling bath isremoved and the mixture is stirred at room temperature for 2 hours. Themixture is then filtered under a blanket of nitrogen into a three-neck,one-liter, round bottom flask fitted with a sintered glass funnel,vacuum-nitrogen inlet, and a mechanical stirrer. Additional anhydrousether (2×50 ml) is used to wash the precipitate of triethylammoniumhydrochloride. The funnel containing the precipitate is replaced by adropping funnel and the etheral filtrate of dibenzyl (4S)-N-trimethylsilyl-aspartate is cooled in an ice bath and stirred under a nitrogenatmosphere while 2.1M t-butyl magnesium chloride in ether (48 ml, 0.1mole) is added drop wise over 9 minutes. A gummy precipitate formsduring the addition. The cooling bath is then removed and the mixture isallowed to stand at room temperature overnight.

The mixture is cooled in an ice-bath and stirred vigorously whileammonium chloride saturated 2N hydrochloric acid (100 ml) is added overa few minutes. After stirring vigorously several more minutes, themixture is diluted with water (100 ml) and ethyl acetate (100 ml) andthe layers are separated. The aqueous portion is extracted with ethylacetate (2×100 ml). The combined organic solution is washed with water(100 ml), 5% aqueous sodium bicarbonate (100 ml), and brine (100 ml),dried with magnesium sulfate, filtered, and evaporated under vacuum to ayellow semi-solid. Crystallization of this material from methylenechloride (100 ml)-petroleum ether (300 ml) provides the azetidinoneproduct (8.2 g) as an off-white powder. The mother liquors areevaporated and the residue crystallized from diethyl ether to affordadditional product (2.5 g) as a pale yellow product. The two crops arecombined and recrystallized from methylene chloride to yield benzyl(4S)-azetidin-2-one-4-carboxylate (9.5 g) as nearly colorless crystals:mp 139°-141° C.; [α]_(D) =-40.5° (C2.0 in CHCl₃); IR (CHCl₃) 3425, 1778,1746 cm⁻¹ ; ¹ H NMR (CDCl₃) δ3.00 (ddd, H-3β), 3.35 (ddd, H-3α), 4.20(dd, H-4), 5.22(s, CH₂ φ), 6.48 (m, NH), 7.35 (s, phenyl); mass spectrumm/e 205 (M⁺), 163, 91, 70, 43.

What is claimed is:
 1. A process for preparing: ##STR31## and itspharmaceutically acceptable salt and ester derivatives;comprising:cyclizing: ##STR32## to form: ##STR33## followed byactivating to form: ##STR34## followed by reacting with HSCH₂ CH₂ NHR¹ ;wherein X is a leaving group; R¹ is hydrogen or a protecting group; andR is a protecting group.